Habegger K.M.,University of Cincinnati |
Grant E.,University of Cincinnati |
Pfluger P.T.,University of Cincinnati |
Pfluger P.T.,Institute for Diabetes and Obesity |
And 7 more authors.
Frontiers in Endocrinology | Year: 2011
Objective: Ghrelin, a stomach-derived, secreted peptide, and its receptor (growth hormone secretagogue receptor, GHSR) are known to modulate food intake and energy homeosta- sis. The ghrelin system is also expressed broadly in cardiovascular tissues. Since ghrelin has been associated with anti-inflammatory and anti-atherogenic properties, but is also well known to promote obesity and impair glucose metabolism, we investigated whether ghrelin has any impact on the development of atherosclerosis.The hypothesis that endogenous ghrelin signaling may be involved in atherosclerosis has not been tested previously. Methods and Results: We crossed ghrelin receptor knockout mice (GHSr-/-)intoalow- density lipoprotein receptor-null (Ldlr-/-) mouse line. In this model, atherosclerotic lesions were promoted by feeding a high-fat, high-cholesterol Western-type diet for 13 months, following a standard protocol. Body composition and glucose homeostasis were similar between Ldlr-/- and Ldlr/GHSR-/-ko mice throughout the study. Absence or presence of GHSr did not alter the apolipoprotein profile changes in response to diet exposure on an LDLRko background. Atherosclerotic plaque volume in the aortic arch and thoracic aorta were also not affected differentially in mice without ghrelin signaling due to GHSR gene disruption as compared to control LDLRko littermates. In light of the associations reported for ghrelin with cardiovascular disease in humans, the lack of a phenotype in these loss-of-function studies in mice suggests no direct role for endogenous ghrelin in either the inhibition or the promotion of diet-induced atherosclerosis. Conclusion: These data indicate that, surprisingly, the complex and multifaceted actions of endogenous ghrelin receptor mediated signaling on the cardiovascular system have minimal direct impact on atherosclerotic plaque progression as based on a loss-of-function mouse model of the disease. © 2011 Habegger, Grant, Pfluger, Perez-Tilve, Daugherty, Bruemmer, Tschöp and Hofmann.
Heppner K.M.,University of Cincinnati |
Muller T.D.,University of Cincinnati |
Kirchner H.,University of Cincinnati |
Perez-Tilve D.,University of Cincinnati |
And 5 more authors.
Journal of Endocrinological Investigation | Year: 2013
Background: Ghrelin is a gastrointestinal peptide that promotes a positive energy balance. The enzyme ghrelin O-acyltransferase (GOAT) esterifies an n-octanoic acid to the peptide, thereby enabling ghrelin to bind and activate the ghrelin receptor. Although ghrelin has previously been implicated in the control and maintenance of body core temperature (BCT), the role that this acylation may play in thermoregulation has not been examined. Aim:We aimed to investigate the endogenous role of ghrelin acylation in thermoregulation. Methods: In this study, we exposed mice lacking the enzyme GOAT as well as wild-type (WT) control mice to cold temperatures under ad libitum and fasting conditions. Additionally, we investigated the role of GOAT in metabolic adaptation to cold temperatures by analyzing BCT and energy metabolism in mice with and without GOAT that were progressively exposed to low ambient temperatures (31-7 C). Results: We find that regardless of nutritional status, mice lacking GOAT maintain a similar BCT as their WT counterparts during an 8 h cold exposure. Furthermore, mice lacking GOAT maintain a similar BCT and metabolic adaptation asWT controls during acclimatization to low ambient temperatures. Conclusions: We conclude that the absence of the enzyme GOAT does not play a significant role in maintenance of BCT or metabolic adaptation during exposure to low external temperatures. (J. Endocrinol. Invest. 36: 180-184, 2013).
Barlow J.,University of Plymouth |
Jensen V.H.,University of Plymouth |
Jastroch M.,Institute for Diabetes and Obesity |
Affourtit C.,University of Plymouth
Biochemical Journal | Year: 2016
It has been well established that excessive levels of glucose and palmitate lower glucose-stimulated insulin secretion (GSIS) by pancreatic β-cells. This β-cell 'glucolipotoxicity' is possibly mediated by mitochondrial dysfunction, but involvement of bioenergetic failure in the pathological mechanism is the subject of ongoing debate. We show in the present study that increased palmitate levels impair GSIS before altering mitochondrial function. We demonstrate that GSIS defects arise from increased insulin release under basal conditions in addition to decreased insulin secretion under glucose-stimulatory conditions. Real-time respiratory analysis of intact mouse pancreatic islets reveals that mitochondrial ATP synthesis is not involved in the mechanism by which basal insulin is elevated. Equally, mitochondrial lipid oxidation and production of reactive oxygen species (ROS) do not contribute to increased basal insulin secretion. Palmitate does not affect KCl-induced insulin release at a basal or stimulatory glucose level, but elevated basal insulin release is attenuated by palmitoleate and associates with increased intracellular calcium. These findings deepen our understanding of β-cell glucolipotoxicity and reveal that palmitate-induced GSIS impairment is disconnected from mitochondrial dysfunction, a notion that is important when targeting β-cells for the treatment of diabetes and when assessing islet function in human transplants. © 2016 Authors; published by Portland Press Limited.